Sex differences have been previously reported in preclinical and clinical studies of cocaine abuse. While relapse to cocaine use following abstinence is the most significant impediment in the treatment of dependence, limited attention has been given as to whether sex differences exist in relapse to cocaine seeking after prolonged abstinence. Consistent with clinical evidence, laboratory animal studies have demonstrated that there are sex differences in cocaine self-administration and in the reinstatement of cocaine-seeking behavior. Relative to males, females have been reported to exhibit higher levels of responding for cocaine, higher levels of extinction responding, higher levels of reinstatement following reexposure to small amounts of cocaine but either the same or lower levels reinstatement following exposure to cues associated with cocaine intake. Further, females show higher levels of initial and sensitized cocaine-induced locomotion than do males. Recent research has increasingly focused on time-dependent changes in the nervous system following demonstrations that cocaine-seeking increases during drug abstinence. This "incubation of craving" effect has also been observed in clinical populations and is thought to precipitate relapse to drug taking. Given the sex differences in other animal models of relapse vulnerability, it is likely that sex differences contribute to the neuroadaptations underlying the incubation of drug craving. Accordingly, the proposed project will investigate the time course of cocaine-seeking during abstinence from cocaine self-administration in male and female rats. It is predicted that females will exhibit enhanced incubation. These findings will further our understanding of the relation between sex differences and behavioral plasticity involved in drug addiction. These initial experiments will form the bases of subsequent studies examining the organizational and activational effects of gonadal hormones and the neuroendocrine bases of sex differences in time-dependent neuroadaptations. [unreadable] [unreadable]